A number of observational and experimental studies have shown that an inflammatory oxidative environment in the cardiovascular system can lead to pathologic changes in the endothelium and contribute to atherosclerosis. Antioxidant nutrients are presumed likely to contribute to a decrease of endothelial dysfunction and to diminish the incidence of cardiovascular events. However, the previous use of antioxidant supplements in clinical trials (e.g., Vitamins E and C, beta-carotene) has yielded disappointing and controversial results. Despite the null findings from recent trials, the biological plausibility of potential benefits from antioxidants remains strong. Continued work is needed in trying to identify specific antioxidants that are effective therapeutic agents. OBJECTIVE: This study will determine whether a dietary supplement containing glutathione will lower levels of inflammatory markers, and whether the presence or absence of supplemental arginine will add to the effectiveness of the glutathione therapy. DESIGN: This is a randomized, double-blind, placebo-controlled, parallel-arm, feasibility study. Ninety adults with Metabolic Syndrome will be randomly assigned for 8 weeks to either: 1) glutathione (GSH, n=30), 2) glutathione + arginine (GSH+Arg, n=30) or placebo (Plac, n=30). Data will be collected at baseline, 2, 4, and 8 weeks. Primary study outcomes are serum markers of inflammation including monocyte chemoattractant protein-1 (MCP-1), interleukin 6 (IL-6), tumor necrosis factor-alpha (TNF-1) and soluble intercellular adhesion molecule-1 (sICAM-1). Secondary outcomes include blood pressure, blood cholesterol, fasting insulin, serum isoprostanes (a measure of oxidative stress) and s-nitrosyl glutathione (a stable, nitric oxide containing compound). IMPLICATIONS: If glutathione, +/- arginine, can effectively lower inflammatory markers, this would suggest a safe and relatively inexpensive therapy to reduce the risk of cardiovascular disease. Recent studies have shown that oxidative stress and the inflammation associated with it are very common in the general population, and so any beneficial therapies found in this area would have widespread benefits. PUBLIC HEALTH RELEVANCE: The major purpose of this study is to examine the effects of an antioxidant dietary supplement (glutathione) with or without an amino acid dietary supplement (arginine) on markers of inflammation among adults with elevated cardiovascular disease risk factors. If the glutathione, or its combination with arginine, can successfully decrease the levels of these inflammatory blood markers, this would suggest a possible preventive therapy for cardiovascular disease that would be relatively safe and inexpensive with widespread availability for the general public.